Structure based designing of triazolopyrimidone-based reversible inhibitors for kinases involved in NSCLC

Article abstract of DOI:10.1016/j.bmcl.2019.05.004

Secondary acquired mutant EGFR (L858R-T790M)overexpressed NSCLC forms one of the prevalent form of resistant NSCLC. Another subset of resistant NSCLC includes amplified cMET in mutant EGFR derived tumours. Thus, in continuation to our previous work on the

Full text of DOI:10.1016/j.bmcl.2019.05.004

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure based designing of triazolopyrimidone-based reversible inhibitors
for kinases involved in NSCLC
⁎
Pankaj Kumar Singha, Dasharath Chaudharib, Sanyog Jainb, Om Silakaria,
a Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India
b Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, NIPER, SAS Nagar, Mohali, Punjab, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Secondary acquired mutant EGFR (L858R-T790M) overexpressed NSCLC forms one of the prevalent form of
resistant NSCLC. Another subset of resistant NSCLC includes amplified cMET in mutant EGFR derived tumours.
Thus, in continuation to our previous work on these two major targets of resistant NSCLC, i.e., EGFR (L858R-
T790M) and cMET, we are hereby reporting reversible inhibitors of these kinases. Out of 11 lead molecules
reported in our previous study, we selected triazolo-pyrimidone (BAS 09867482) scaffold for further develop-
ment of small molecule dual and reversible inhibitors. Analogues of lead with different substituents on the side
ring were sketched and docked in both the target kinases, followed by molecular dynamic simulations.
Analogues maintaining hydrophobic interaction with M790 in secondary acquired mutant EGFR (L858R-T790M)
were selected and duly synthesized. In vitro biochemical evaluation of these molecules against EGFR (L858R-
T790M) and cMET kinase, along with EGFR (L858R) kinase disclosed that three molecules were having sig-
nificant dual kinase inhibitory potential with IC50 values well below 100 nM. Further, in vitro anti-proliferative
assay against three cell lines (A549, A431 and H460) was performed. Out of all, two compounds were having
significant potency against these cell lines.
EGFR (T790M)
cMET
Triazolopyrimidone
NSCLC
Molecular dynamics
Small molecule reversible inhibitors such as gefitinib and erlotinib
are well established for the clinical use in the treatment of EGFR-acti-
vating mutations (L858R) positive non-small cell lung cancer
(NSCLC).1,2 However, resistance to these drugs is commonly observed
via an acquired secondary mutation, EGFR T790M,3 known as the
gatekeeper mutation. Actually, this secondary acquired mutation re-
sults in restoration of ATP affinity,4 similar to wild-type (WT) EGFR,
thereby preventing binding of the reversible inhibitors in the catalytic
domain at higher ATP concentrations.5 Other major mechanism iden-
tified as the cause for the failure of these molecules include parallel
signalling via amplified c-MET in the L858R mutant EGFR over-
expressed lung cancer.6–8
domain of the double mutant kinase. But as covalent inhibitors are site
specific in nature, any alteration in target residue can limit their effi-
cacy and expectedly in recent years, another acquired mutation, C797S
in EGFR, has been disclosed and is reported to make third generation
inhibitors ineffective.10
Recent reports have suggested that administration of irreversible
inhibitors in previously resistant NSCLC expressing double mutant
EGFR (T790M/L858R), results in triple mutant EGFR with additional
C797S mutation, developing resistance against all currently available
small molecular inhibitors based therapies except for combination
therapy with the anti-EGFR antibody, cetuximab.11 Also, irreversible
inhibitors cannot be used in first line therapy due to reports suggesting
that administration of dacomitinib in EGFR mutant (L858R) lung
cancer can directly induce T790M or C797S secondary mutations.10
Thus development of reversible small molecule inhibitors which have
more binding affinity than ATP towards mutant EGFR (both single and
double) seems to be a more rational and logical step. Additionally,
targeting concomitantly overexpressing molecular targets which assist
in cross-signalling pathways may yield exciting result. Clinical trials are
currently underway to test the effects of dual inhibition of c-MET and
EGFR to overcome this mode of resistance.12
Initial work on secondary acquired EGFR was focussed on irrever-
sible inhibitors containing a michael acceptor functional group.9 Afa-
tinib, a second-generation inhibitor, was one of the early member of
this family but unfortunately, these inhibitors resulted in toxicity due to
non-selective inhibition of wild-type EGFR and/or other kinases.5 This
further led to the development of third generation kinase inhibitors,
which are covalent but are selective towards double mutant EGFR.
Selectivity in these agents is claimed due to the hydrophobic interac-
tions between the inhibitors and mutated residue M790 in the catalytic
⁎ Corresponding author.
E-mail address: omsilakari@gmail.com (O. Silakari).
https://doi.org/10.1016/j.bmcl.2019.05.004
Received 12 March 2019; Received in revised form 24 April 2019; Accepted 5 May 2019
0960-894X/©2019ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:PankajKumarSingh,etal.,Bioorganic&MedicinalChemistryLetters,https://doi.org/10.1016/j.bmcl.2019.05.004

P.K. Singh, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
Hence, following our previous work,13 we focussed on designing
molecules which may inhibit c-MET and secondary acquired mutant
EGFR (L858R/T790M) reversibly. Focus was laid on the fact that sen-
sitivity towards inhibitors is not lost in EGFR (L858R/T790M) rather
the affinity towards ATP increases. Thus, special attention was given to
the fact that molecules having hydrophobic interaction with mutant
residue M790 provide selectivity to the molecules and also enhance the
binding affinity towards EGFR (L858R/T790M). Thus we attempted to
design molecules with higher affinity towards EGFR (L858R/T790M)
along with c-MET using in-silico techniques.
In continuation to the previous in-silico study by our group to
identify reversible dual/multi inhibitor of EGFR (L858R/T790M) and
cMET, out of previously reported 11 hits identified for putative EGFR
(L858R/T790M) and cMET inhibitory potential, triazolo-pyrimidone
(BAS 09867482) was selected for further study. Several analogues of
this lead molecule were sketched and docked in the PDBs of both the
target kinases. Derivatives maintaining the key interactions in both the
targets, such as hydrogen bond interactions with Met793 and Lys745 in
EGFR (L858R/T790M) and, with Met1160 and Tyr1230 in cMET, were
selected and subjected to molecular dynamic simulations for the time
period of 30 ns and calculation of MM-GBSA score (binding energies).
All the compounds showed good docking scores (−CDOCKER energy)
in both the kinases; ranging from 28.74–12.19 within the EGFR
(L858R/T790M) protein and 21.41–12.64 in cMET.
Fig. 1. RMSD plot of 14c in complex with EGFR (L858R/T790M) for the time
period of 30 ns.
Molecular dynamic simulations in EGFR (L858R/T790M) revealed
that carbonyl group in the pyrimidone nucleus of the designed com-
pounds act as acceptor group and interacts via hydrogen bond with
Met793, similarly in few compounds nitrogen of the triazole ring acts as
a hydrogen bond acceptor for Met793. While, eNH in the pyrimidone
nucleus acts as hydrogen bond donor and interacts with hinge region
amino acids including Met793, Lys745 and Glu762. While, in c-MET,
key interactions included hydrogen bond interaction between carbonyl
of the pyrimidone and nitrogen of the triazole ring with residues such as
Met1160 and Lys1232. Additionally, π-π stacking between fused tria-
zolopyrimidone and Tyr1159, and other residues were also observed. A
key fact considered during screening via molecular dynamic simula-
tions was the hydrophobic interaction of the designed molecules with
mutated gate keeper residue, M790 which is essential for the selectivity
and potency of molecules against double mutant EGFR (L858R/
T790M). Osimertinib, recently reported EGFR (L858R/T790M) in-
hibitor, was based on the expectation that molecules with hydrophobic
interaction with the mutant M790 gatekeeper residue could result in
potent and selective inhibitors.7 Thus molecules (ten) which were
maintaining varied levels of hydrophobic interaction with mutated gate
keeper residue, M790 in EGFR (L858R/T790M) were selected for
synthesis and biological evaluations. Additionally, the RMSD values of
the protein backbone atoms in complex with top compounds (14c and
14d), revealed complexes to be very stable in cases of EGFR (L858R/
T790M) as shown in the graphs of the same plotted against time (Figs. 1
and 2).
Fig. 2. RMSD plot of 14d in complex with EGFR (L858R/T790M) for the time
period of 30 ns.
with ethyl acetoacetate in acetic acid as solvent under reflux, to afford
final compounds. The obtained compounds were purified via re-
crystallization. All the compounds were characterized by IR, 1H NMR
and 13C NMR. In IR spectrum, the triazolo-pyrimidone derivatives
showed the presence of strong absorption bands of C]O ∼1680 and
C]N from ∼1650 to ∼1560 cm−1. The synthesis of final compounds
were confirmed in 1H NMR. Almost each spectrum showed presence of
singlet of one proton at ∼5.7 ppm, present in pyrimidone nucleus. Rest
of the aromatic protons were observed in similar pattern from ∼7.0 to
∼8.4 ppm. A singlet of two proton at ∼4.5 ppm was also observed in
each compound for eCH2 of the benzyl groups. 13C spectrum exhibited
characteristic peak at ∼163 ppm for pyrimidone. Rest of the aromatic
carbons were observed from 120 to 134 ppm with a characteristic peak
at 98 ppm for C-6 carbon. Similarly, mass spectrometry also showed
quasi ion peaks at expected m/z values.
The 3D interaction diagram of the best designed molecules 14c in
cMET and in EGFR (L858R/T790M) are shown in Figs. 3 and 4, re-
spectively. Finally, MM-GBSA score were also calculated to validate the
derivatives selected for further study. In EGFR (L858R/T790M), the
binding affinity determined via MM-GBSA score correlated positively
with the degree of hydrophobic interactions of the derivatives with
M790, ranging from −72.857 to −59.723 Kcal/mol. While in cMET,
almost all the derivatives were found to possess significant and con-
sistent binding affinity ranging from −93.323 to −63.997 Kcal/mol
(Table 1).
For the synthesis of molecules pertaining to Scheme 1, in the first
step alkylation of 5-amino-1,2,4-triazole-3-thiol was performed by
treating with variedly substituted benzyl chlorides in the presence
K2CO3 using acetone as solvent to yield different benzylated 5-amino-
1,2,4-triazole-3-thiols. In the next step, cyclization of the obtained
benzylated 5-amino-1,2,4-triazole-3-thiols was performed, by reacting
For the in vitro evaluation of kinase inhibitory potential of the
synthesized compounds, enzymatic assay against EGFR (L858R/
T790M) and cMET was performed, additionally evaluation against
2

P.K. Singh, et al.
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Table 1
Designed compounds with their binding energies and predicted activity.
S. No. Compound MM-GBSA
Predicted
activity-
MM-GBSA
binding
energy
Predicted
activity-
binding
energy
(EGFR)
EGFR (µM)
cMET (µM)
cMET
1
14a
14b
14c
14d
14e
14f
14g
14h
14i
−62.123
−71.074
−73.211
−67.881
−64.035
−72.857
−69.603
−62.021
−59.723
−71.778
0.364
0.251
0.251
0.248
0.247
0.247
0.250
2.669
0.371
0.247
−63.997
−77.894
−84.968
−85.737
−82.212
−91.339
−66.791
−75.084
−82.309
−93.323
0.831
0.131
0.114
0.233
0.230
0.163
0.347
0.830
0.829
0.159
2
3
4
5
6
7
8
9
10
14j
T790M), 0.080 µM against EGFR (L858R) and 0.050 µM against cMET.
Similarly, trifluoromethyl substitution (14d) at meta position on benzyl
ring also resulted in significant multi kinase inhibitory potential with
IC50 values of 0.084, 0.081 and 0.094 µM against EGFR (L858R/
T790M), EGFR (L858R) and cMET, respectively. However, upon in-
creasing the size of substituent, as in case of tert-butyl group, activity
against EGFR (L858R/T790M) reduced to 0.188 µM but was equally
effective against others with IC50 values below 100 nM. Substitution of
fluoro group at para position resulted in potent inhibitor of EGFR
(L858R/T790M) with IC50 value of 0.056 µM but did not possess
equally good activity in cMET with IC50 value of 0.203 µM. Upon re-
placement of fluoro with chloro, activity in EGFR (L858R/T790M) re-
duced with slight improvement in cMET inhibitory potential with IC50
value of 0.113 µM. However, upon substituting 4-chloro benzyl with
2,4-dichloro benzyl, selective cMET inhibitor was obtained with IC50
value of 0.042 µM (Table 2). Overall inhibitory potential of the de-
signed molecules against EGFR (L858R/T790M) can be correlated with
the degree of their hydrophobic interactions between designed analo-
gues and M790 (Fig. 5).
Fig. 3. 3D interaction diagram along with contact summary of 14c in complex
with cMET.
Finally, the synthesized compounds were subjected to in-vitro anti-
proliferative evaluation against three cancer cell lines i.e., A549, A431
and H460. The values are expressed as median effect dose in µM at
which 50% cells are inhibited, calculated by CalcuSyn software 2.1
(Biosoft, Ferguson, MO, USA). Erlotinib was used as standard in this
evaluation. Obtained results are expressed as
%
viability
(Mean
S.D.) v/s different concentration of the compounds (14a–j) in
the plotted graphs. Corresponding IC50 value for each compound is also
calculated and is given in Table 3. Against A431 cell line, 14c, 14e and
14j were found to possess significant inhibitory potential amongst all
the compounds. 14c was found to possess commendable activity at all
the concentrations with only 71.72%, 50.73%, 38.77% and 17.68% cell
viability at 10 µM, 20 µM, 30 µM and 40 µM concentration, respec-
tively. Similarly, 14e also showed good anti-proliferative activity at all
the concentrations, with only 75.85%, 62.47%, 41.66% and 32.47%
cell viability at 10 µM, 20 µM, 30 µM and 40 µM concentration, re-
spectively (Fig. 6). The anti-proliferative potential of some of the de-
signed compound against A431, an EGFR-overexpressed cell line, was
in coherence with the obtained in-silico results. A strong hydrogen bond
with Met793, a key residue in the catalytic domain of EGFR, can be
considered responsible for improved activity of 14c having IC50 value
of 17.29 μM. Similarly, methyl substituted compound 14e and dichloro
substituted compound 14j, both hydrophobic group substituted deri-
vatives were found to possess significant anti-proliferative activity with
the IC50 value of 15.80 μM and 18.18 μM, respectively. However,
compounds with hydro-neutral substitutions (nitro-substituted com-
pound 14h and 14i) showed poor activity with IC50 values > 40 µM
(Table 3).
Fig. 4. 3D interaction diagram along with contact summary of 14c in complex
with EGFR (L858R/T790M).
EGFR (L858R) was also performed, which is involved in the develop-
ment of NSCLC in around 50% patients in the first place. Appropriate
standards (i.e. erlotinib and XL-184), controls and test samples were
utilized. The test compounds were used at the concentration of 0.01,
0.1 and 1 µM, and inhibitory potential was characterized by IC50 value.
Compound 14c with isopropyl substitution on the benzyl ring on the
triazolopyrimidone scaffold was found to possess excellent multi kinase
inhibitory potential with IC50 value of 0.062 µM against EGFR (L858R/
Against A549 cell line, 14c and 14j were found to possess sig-
nificant inhibitory potential amongst all the compounds. 14c was found
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Scheme 1. Synthetic protocol for the designed
compounds.
Table 2
In-vitro kinase inhibitory data of designed compounds against EGFR (L858R/T790M), EGFR (L858R), cMET.
S. No.
Compound ID
R
EGFR (L858R/T790M) (µM
SD)
EGFR (L858R) (µM
SD)
cMET (µM
SD)
1
14a
-4-F
0.056 ( 0.003)
0.188 ( 0.021)
0.062 ( 0.003)
0.084 ( 0.004)
0.168 ( 0.004)
0.182 ( 0.025)
0.059 ( 0.004)
0.076 ( 0.003)
0.077 ( 0.002)
0.141 ( 0.023)
0.907 ( 0.011)
–
0.052 ( 0.004)
0.086 ( 0.004)
0.080 ( 0.005)
0.081 ( 0.019)
0.311 ( 0.022)
0.054 ( 0.005)
0.131 ( 0.003)
0.107 ( 0.004)
0.157 ( 0.026)
0.141 ( 0.005)
0.032 ( 0.009)
–
0.203 ( 0.003)
0.065 ( 0.003)
0.050 ( 0.004)
0.094 ( 0.002)
0.079 ( 0.002)
0.113 ( 0.021)
0.092 ( 0.004)
0.104 ( 0.018)
0.089 ( 0.002)
0.042 ( 0.003)
–
2
14b
-4-C(CH3)3
-4-CH(CH3)2
-3-CF3
-CH3
3
14c
4
14d
5
14e
6
14f
-4-Cl
7
14g
-3-Cl
8
14h
-4-NO2
-3-NO2
-2,4-di-Cl
–
9
14i
10
11
12
14j
Erlotinib
XL-184
–
0.030 ( 0.010)
where IC50 represents the dose of compound in µM required to produce 50% inhibition of respective enzymes.
Bold values represent the most potent compound.
a)
b)
c)
d)
Fig. 5. Histogram representing interaction fraction throughout the time period of 30 ns in EGFR (L858R/T790M) with different compounds; a) 14a; b) 14c; c) 14d; d)
14g.
to possess commendable activity at all the concentrations with only
89.65%, 79.64%, 65.27% and 43.36% cell viability at 10 µM, 20 µM,
30 µM and 40 µM concentration, respectively. Similarly, 14j also
showed good anti-proliferative activity at all the concentrations, with
only 88.31%, 76.95%, 61.18% and 46.82% cell viability at 10 µM,
20 µM, 30 µM and 40 µM concentration, respectively (Fig. 7). The anti-
proliferative potential of some of the designed compounds (14c and
14j) against A549 was found comparable to FDA-approved kinase in-
hibitor erlotinib (Table 3). Isopropyl, a hydrophobic group, substituted
compound 14c showed IC50 value of 35.21 µM. Similarly, dichloro-
substituted compound 14j was found to possess significant anti-
proliferative activity with the IC50 value of 34.93 μM. Similar to A431,
hydro-neutral nitro-substituted compounds, 14h and 14i showed poor
activity with IC50 values > 80 μM (Table 3).
Against H460 cell line, 14c and 14j were found to possess sig-
nificant inhibitory potential amongst all compounds. 14c was found to
possess commendable activity at all the concentrations with only
86.66%, 71.64%, 56.05% and 41.81% cell viability at 10 µM, 20 µM,
30 µM and 40 µM concentration, respectively. Further 14j also showed
good anti-proliferative activity at all the concentrations, with only
83.54%, 65.65%, 50.97% and 34.90% cell viability at 10 µM, 20 µM,
30 µM and 40 µM concentration, respectively (Fig. 8). The anti-
4

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Table 3
In-vitro anti-proliferative data of compounds (14a-j) against different cell lines.
S. No.
Compound ID
R
A431 (µM
> 40
SD)*
A549 (µM
> 80
SD)*
H460 (µM
> 80
SD)*
1
14a
14b
14c
-4-F
2
-4-C(CH3)3
-4-CH(CH3)2
-3-CF3
-CH3
24.41 ( 2.14)
17.29 ( 2.83)
21.76 ( 2.63)
15.80 ( 2.54)
32.47 ( 2.64)
> 40
60.51 ( 3.60)
35.21 ( 2.69)
71.95 ( 2.44)
50.08 ( 2.03)
61.35 ( 1.05)
> 80
58.95 ( 2.33)
31.83 ( 2.63)
65.76 ( 1.12)
49.87 ( 1.20)
56.49 ( 1.24)
> 80
3
4
14d
14e
14f
5
6
-4-Cl
7
14g
14h
14i
-3-Cl
8
-4-NO2
-3-NO2
-2,4-di-Cl
–
> 40
> 80
> 80
9
> 40
> 80
> 80
10
11
14j
18.18 ( 1.87)
5.14 ( 3.52)
34.93 ( 1.89)
27.55 ( 1.24)
27.22 ( 1.51)
24.60 ( 1.31)
Erlotinib
Bold values represent the most potent compound.
* The values represent IC50 values, expressed as median effect dose in µM at which 50% cells are inhibited, calculated by CalcuSyn software 2.1.
% viability (A431) v/s different conc. of 14a-j
120
100
80
60
40
20
0
14a
14b
14c
14d
14e
14f
14g
14h
30μM
14i
40μM
14j
Erloꢀnib
1μM
2.5μM
5μM
10μM
20μM
Fig. 6. Percent viability of A431 in response to treatment with synthesized compounds at concentrations of 1 μM, 2.5Μm, 5 μM, 10 μM, 20 μM, 30 μM and 40 μM for
time duration of 48 h. Data is expressed as mean values S.D. of three independent experiments.
% viability (A549) v/s different conc. of 14a-j
120
100
80
60
40
20
0
14a
14b
14c
10μM
14d
20μM
14e
30μM
14f
40μM
14g
60μM
14h
80μM
14i
14j
Erloꢀnib
Fig. 7. Percent viability of A549 in response to treatment with synthesized compounds at concentrations of 10 μM, 20Μm, 30 μM, 40 μM, 60 μM and 80 μM for time
duration of 48 h. Data is expressed as mean values
S.D. of three independent experiments.
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% viability (H460) v/s different conc. of 14a-j
120
100
80
60
40
20
0
14a
14b
14c
10μM
14d
20μM
14e
30μM
14f
40μM
14g
60μM
14h
80μM
14i
14j
erloꢀnib
Fig. 8. Percent viability of H460 in response to treatment with synthesized compounds at concentrations of 10 μM, 20 μM, 30 μM, 40 μM, 60 μM and 80 μM for time
duration of 48 h. Data is expressed as mean values
S.D. of three independent experiments.
Table 4
Various pharmacokinetic parameters predicted for the designed analogues.
Compound
logS
logD
logP
caco2
VD
PPB
CL
T
Pgp
HIA
14a
14b
14c
14d
14e
14f
14g
14h
14i
−3.521
−4.075
−4.029
−4.066
−3.62
1.522
2.551
2.358
1.93
2.157
3.316
3.142
3.037
2.327
2.672
2.672
1.927
1.927
3.325
−4.551
−4.584
−4.606
−4.505
−4.556
−4.539
−4.504
−4.573
−4.526
−4.473
−0.421
0.064
88.671
92.9
1.136
1.542
1.449
1.33
1.583
2.056
1.804
1.746
1.562
1.719
1.784
1.3
0.12
0.796
0.737
0.748
0.794
0.767
0.794
0.794
0.644
0.644
0.798
0.133
0.064
0.113
0.101
0.03
−0.04
90.423
89.415
89.358
87.642
87.514
87.606
87.878
88.825
−0.541
−0.303
−0.341
−0.334
−0.712
−0.677
−0.32
1.81
1.119
0.869
0.837
0.76
−3.856
−3.84
1.806
1.814
1.34
0.056
0.046
0.07
−3.514
−3.523
−4.291
1.335
2.282
0.73
1.355
1.837
14j
0.821
0.012
*VD; volume of distribution, PPB; plasma protein binding, CL; clearance, T; half-life, Pgp; probability of Pgp substrate, HIA; probability of human intestinal ab-
sorption.
proliferative potential of some of the designed compounds (14c and
14j) against H460, a less-kinase inhibitors susceptible cell line, was
found comparable to FDA-approved kinase inhibitor erlotinib (Table 3).
Isopropyl, an electron donating group, substituted compound 14c
showed IC50 value of 31.83 µM. While 14j, a dichloro substituted
compound, was found to possess significant anti-proliferative activity
with the IC50 value of 27.22 μM. However, compounds (14h and 14i)
with nitro-substitution showed poor activity with IC50 values > 80 μM
(Table 3).
against EGFR (L858R/T790M) was found to be in co-relation with the
results obtained in MD simulations. Finally the designed compounds
were evaluated for their in-vitro anti-proliferative potential against
three cell lines (A549, A431 and H460). Out of all compound 14c and
14j were found to possess significant inhibitory potential, comparable
to FDA-approved drug erlotinib.
Declaration of Competing Interest
Authors declare no conflict of interest.
Acknowledgement
Finally, the pharmacokinetic parameters of the analogues were also
predicted using a freely available web interface for systematic ADMET
evaluation, ADMETlab,14 as given in Table 4. Results suggest that al-
though the compounds possess good solubility (logS) and distribution
coefficient (logD), the permeability (caco2) is sub-optimal and can be
enhanced to improve the potency of the molecules.
This work was supported by the DBT (Department of Biotechnology,
New Delhi, India) under Grant No. BT/PR8275/BID/7/455/2013.
In the conclusion, structure-driven computational and medicinal
chemistry design strategy was utilized in this study. Previously pub-
lished study was utilized for the selection of lead molecule with dual
kinase inhibitory potential. Further in-silico methodology was employed
to design derivatives of the selected lead, keeping in mind the essen-
tiality of hydrophobic interaction between mutated gate keeper residue
and designed molecules to obtain significant inhibitory potential.
Followed by synthesis of designed derivatives, their in-vitro evaluation
against all target kinases was performed. Compound 14c and 14d were
found to possess significant multi-kinase inhibitory potential against
EGFR (L858R), EGFR (L858R/T790M) and cMET. Inhibitory potential
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2019.05.004.
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